Our overall objective is to understand better how the lungs respond to inhaled particles. Since clearance of particles and pathogens from non-ciliated surfaces of the lungs is the main function of alveolar macrophages, and since their behavior may critically influence the pathogenesis of pulmonary diseases, we plan to focus on these cells and their allies with the aim to develop a comprehensive picture of the range of their activity and responsiveness. Knowing that alveolar macrophage populations can vary in overall characteristics under different conditions, we propose to investigate (1) the differentiation of alveolar macrophages in the lungs under ambient conditions, as well as after particle stimulation with special reference to the sequence of events and causative factors leading to the activation of macrophage lysosomes, as well as (2) factors influencing motility, migration, phagocytic behavior, and other characteristics of alveolar macrophage populations. We also plan (3) to compare functional attributes of alveolar macrophages with those of macrophages located on airway surfaces, and in the pulmonary connective tissue and (4) to examine the role of macrophages in influencing particle transport across the bronchial epithelium. Our methods include those of cell biology, biochemistry, and respiratory physiology, including in vivo and in vitro test systems and inhalation technology. Since inhalation is the primary entry route for agents causing environmental, occupational, and infectious diseases, it is important to obtain substantial knowledge about the role of macrophages in alveolar defense and to identify environmental and experimental factors that alter macrophage function and in this way influence the possible development of pulmonary injury.